TENS in Fibromyalgia: From Physical Therapy & fundamental - - PowerPoint PPT Presentation

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TENS in Fibromyalgia: From fundamental neurobiology to pragmatic trial

Leslie J. Crofford, MD Wilson Family Chair in Medicine Professor of Medicine and Pathology, Microbiology & Immunology Chief, Division of Rheumatology & Immunology Kathleen Sluka, PT, PhD, FAPTA Kate Daum Research Professor Dept of Physical Therapy and Rehabilitation Science

Physical Therapy & Rehabilitation Science

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Disclosures

• Consulting:

Sluka (GSK/Novartis, Pfizer)

• Speakers Bureau:

None

• Grant Funding:

Sluka (Am Pain Soc/Pfizer)

• Legal Work:

None

• Stock, Royalties, etc:

Crofford (Up to Date), Sluka (IASP Press)

Physical Therapy & Rehabilitation Science

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Acknowledgements

UG3 AR076387 UM1 AR063381 U54 TR001356 UL1 TR000445 NCT 01888640 DJO, Inc TENS units and electrodes

Physical Therapy & Rehabilitation Science

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Presentation Outline

• What is fibromyalgia?
• Central (nociplastic) pain
• Basic pain mechanisms
• Why TENS?
• Mechanisms of TENS
• Randomized controlled trial
• FAST
• Pragmatic trial
• FM-TIPS

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What is fibromyalgia?

Central (nociplastic) pain syndrome

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Diagnosing fibromyalgia

• Symptom of widespread pain
• “Hurt all over”
• 1990 ACR Classification Criteria – “Above and below the waist,

left and right sides or the body, involving the axial skeleton”

• 2016 – “Involving 4 of 5 regions from the widespread pain index”
• Other criteria count number of painful sites
• Symptom/sign of tenderness
• “Painful with gentle touch”
• ACR1990 – 11 of 18 tender points (4 kg/cm2 pressure)
• Skin roll or BP cuff tenderness
• Pain worsened with physical activity

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Diagnosing fibromyalgia

• Chronic fatigue
• Non-refreshing sleep
• Chronic myofascial/visceral pain
• Irritable bowel syndrome
• Interstitial cystitis/bladder pain syndrome
• Temporomandibular pain
• Chronic headache (tension, migraine)
• Etc.
• Depression/anxiety

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Somatic Pain

Noxious impulses being received and transmitted by normal components

• f the sensory nervous system

Neuropathic Pain

Noxious impulses originating from an abnormality in neural structures

Central (Nociplastic) Pain

Innocuous impulses perceived as noxious due to physiologic alterations of neural structures

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Nociplastic Pain

Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain. IASP Definition 2017

• K. Sluka

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Gracely et al. Arthritis Rheum 46:1333-43, 2002

Is the Pain “Real”?

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Evoked Pain Testing in Nociplastic Pain

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Basic Pain Mechanisms

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Transmission Perception

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Central Pain Pathways

• Sensory discriminative
• Somatosensory cortex
• Motivational-Affective
• Cingulate and insular

cortex

• Fear-Emotion
• Amygdala
• Planning, decision-making,

social behavior

• Prefrontal cortex

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Descending Inhibition

• Via RVM and PAG
• Endogenous
• pioids
• Serotonin
• K. Sluka

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Steps in Central Sensitization

• Nociceptive Transmission
• Requires nociceptive input (peripheral pain generator)
• Dependent on excitatory amino acids, tachykinins,

substance P

• Acute Phase Central Sensitization
• Release in block of NMDA receptors
• Activation of kinases via NMDA, NK1, TrkB receptors
• Late Phase Central Sensitization
• Gene transcription locally and diffusely
• Activation of microglia
• Disinhibition
• Altered inhibitory and facilitatory controls from CNS

Woolf, C. Ann Intern Med 2004;140:441-451.

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Why TENS?

Mechanisms suggesting potential benefit in central (nociplastic) pain

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What is TENS?

• Transcutaneous Electrical Nerve Stimulation

TENS is expected to be effective mainly when the unit is active

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nociceptor large afferent TENS spinal cord Recording electrode

Garrison and Foreman. Pain 1994;58:309-315.

High Threshold Neuron

back brush press pinch spikes/sec 10 20 30 40 50

* *

Dorsal Horn Neuron Activity

back brush press pinch spikes/sec 5 10 15 20 25 30

* * *

Wide Dynamic Range Neuron

Ma and Sluka, 2001; Sluka et al., 2005; Garrison and Foreman, 1994, 1996

TENS Reduces Central Excitability

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TENS Activates Endogenous Inhibition: Opioids and Serotonin

Nociceptive neuron

m

Nociceptive neuron (ON cells) Decreased activity

m

GABA Opioid

Gab a-A

Serotonin Neuron Increased activity

To Spinal Cord

5- HT 3 5- HT 2

From RVM serotonin Low Frequency TENS Decreased sensitization

Opioid

From PAG

Mixed frequency, low and high, prevents analgesic tolerance

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TENS Opioid Effects in Humans

Solomon et al., 1980, Leonard et al., 2010; Sjolund and Eriksson, 1974

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TENS for Chronic Musculoskeletal Pain

• Meta-analysis with

data from 29 randomized trials

– Patients had pain from back, hip, neck, and knee – 335 placebo, 474 TENS

• TENS had favorable

pooled effect vs placebo (p<0.0005)

• Out of favor as pain

treatment in PT

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Why TENS in Fibromyalgia?

• Reduces central excitability at the level of the dorsal horn
• High threshold neurons AND wide dynamic range neurons
• Reduces neuronal activation to BOTH innocuous and

noxious stimuli

• Reduces excitatory amino acid (glutamate) release
• Activates descending inhibitory pathways
• PAG-RVM-spinal cord
• Uses endogenous opioids and serotonin

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Randomized, Controlled Trial

Fibromyalgia Activity Study with TENS (FAST)

Dana Dailey PT, PhD

Arthritis Rheumatol. 2020 May;72(5):824-836

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Treatment

• Active TENS parameters
• Butterfly electrodes cervical and lumbar placement
• Asymmetrical biphasic waveform
• Modulating frequency 10-125 Hz
• Variable pulse duration
• Highest “strong but comfortable” intensity
• Instructed to apply at least 2 hours/day during activities

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Placebo and Blinding

• Used Placebo TENS
• Transient unit with short-duration of stimulation of 45s that

ramped down over last 15s

• Blinding script
• Included a No TENS group with Mock TENS during

assessments

• Assessors remained blinded to Active TENS (45% correct),

Placebo TENS (13% correct), and Mock TENS (20% correct)

• Participants blinded to Placebo TENS (49% correct), but

Active TENS correctly identified by 70%

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Main Inclusion Exclusion Criteria

• Inclusion
• Women between 18-70 years old
• Met 1990 criteria for classification of fibromyalgia
• Average pain rating ≥ 4 over last 7 days by NRS at Visit 1

AND Visit 2

• Exclusion
• TENS use in last 5 years
• Contraindications to TENS use

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Study Design

All participants received 4 weeks of Active TENS between Visit 3 and Visit 4

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Outcome Measures

• Secondary
• Resting pain pre/post TENS

during visits

• Disease activity/impact

(FIQR)

• Pain intensity/interference

(BPI: Brief Pain Inventory)

• Pain self-efficacy (PSEQ)
• Pain catastrophizing (PCS)
• Fatigue during movement

and at rest

• Multidimensional fatigue

(MAF)

• Sleep (PSQI)
• Fear of movement (TSK)
• PROMIS-Anxiety
• PROMIS-Depression
• Quality of life (SF-36)
• Self-report physical function

(FIQR-function)

• Performance based physical

function (6WMT, 5TSTS)

• Patient global rating of

change

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Participants

Completed Visit 4: Active TENS (n=75), Placebo TENS (n= 73), No TENS (n=84)

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Active TENS n=103 Placebo TENS n=99 No TENS n=99 p-value Demographic Variables* Age, mean (SD) 44.7 (14.3) 47.2 (12.6) 48.6 (11.8) 0.10 Race, White 92% 92% 92% 0.99 Ethnicity, Not Hispanic 95% 95% 95% 0.99 Married / Living with partner 33% 51% 52% 0.01 Less than college graduate 61% 61% 64% 0.48 Working 55% 45% 58% 0.42 Health Variables Never smoked 82% 80% 70% 0.16 Body mass index (kg/m2) 34.8 (8.7) 33.7 (8.8) 34.0 (8.9) 0.65 Duration of fibromyalgia (yrs) 7 (3-12) 7 (2-14) 7 (4-15) 0.47 Opioids for pain^ 27 (26%) 26 (26%) 26 (26%)

• Baseline Measures

Pain at rest (NRS) 6.2 (1.5) 5.9 (1.4) 6.1 (1.6) 0.33 Fatigue at rest (NRS) 6.8a (2.0) 6.1b (1.8) 6.4ab (2.0) 0.08 FIQ-R 7-day pain 6.7 (1.8) 6.0 (1.6) 6.15 (1.8) 0.02 FIQ-R 59.2a (16.8) 53.7b (15.9) 55.6ab (16.0) 0.05 SF-36 MCS 38.7 (10.0) 40.2 (10.2) 39.5 (10.6) 0.57 SF-36 PCS 32.7 (6.4) 33.3 (6.2) 32.7 (6.6) 0.72 PSQI, z-score 12.6 (3.8) 12.0 (3.8) 11.9 (3.4) 0.38 PCS 23.1 (13.0) 20.4 (12.5) 20.8 (12.1) 0.26 PSEQ 28.2 (13.3) 29.9 (13.1) 29.0 (13.2) 0.67 TSK 36.5 (7.7) 37.1 (8.0) 37.4 (8.3) 0.68

^Enrollment stratified by site and by opioid use

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Movement and Resting Pain/Fatigue

B e fo re D u rin g B e fo re D u rin g 3 4 5 6 7 8

P a in (0 -1 0 )

A ctiv e T E N S P la c e b o T E N S N o T E N S

V is it 2 V is it 3

M o ve m e n t P a in 6 M W T

* *

B e fo re D u rin g B e fo re D u rin g 3 4 5 6 7 8

P a in (0 -1 0 ) V is it 2 V is it 3

M o ve m e n t P a in 5 T S T S

* *

B e fo re D u rin g B e fo re D u rin g 3 4 5 6 7 8

P a in (0 -1 0 ) V is it 2 V is it 3

* *

R e stin g P a in

B e f

• r

e D u r i n g B e f

• r

e D u r i n g 3 4 5 6 7 8

F a tig u e (0 -1 0 ) V is it 2 V is it 3

* *

R e s tin g F a tig u e

A B C D E F

B e f

• r

e D u r i n g B e f

• r

e D u r i n g 3 4 5 6 7 8

F a tig u e (0 -1 0 )

A ctiv e T E N S P la c e b o T E N S N o T E N S

*

M o ve m e n t F a tig u e 6 M W T

V is it 2 V is it 3

B e f

• r

e D u r i n g B e f

• r

e D u r i n g 3 4 5 6 7 8

F a tig u e (0 -1 0 ) V is it 2 V is it 3

M o ve m e n t F a tig u e 5 T S T S

* *

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Patient-reported

• utcomes

Active TENS n=103 Placebo TENS n=99 No TENS n=99 Group Mean Difference (95% CI) P-value Active vs PLACEBO Active vs No TENS

FIQ-R

• 8.48 (-12.92, -4.04)^^
• 3.42 (-6.54, -0.30)^
• 1.39 (-4.40, 1.62)
• 5.06 (-10.44, 0.32)

0.073

• 7.09 (-12.42, -1.77)

0.005

FIQ-R Pain

• 1.3 (-1.8, -0.7)^^
• 0.4 (-0.9, 0.2)
• 0.1 (-0.6, 0.4)
• 0.9 (-1.7, -0.1)

0.018

• 1.2 (-1.9, -0.4)

0.0006

BPI- Interference

• 0.94 (-1.40, -0.48)^^
• 0.26 (-0.73, 0.21)
• 0.29 (-0.74, 0.16)
• 0.68 (-1.33, -0.01)

0.044

• 0.65 (-1.29, -0.01)

0.047

BPI- Intensity

• 0.75 (-1.08, -0.43)^^
• 0.26 (-0.59, 0.07)

0.15 (-0.17, 0.46)

• 0.49 (-0.96, -0.02)

0.035

• 0.90 (-1.35, -0.44)

<0.0001

MAF GFI

• 4.63 (-6.42, -2.84)^^
• 1.46 (-3.29, 0.37)
• 0.26 (-1.98, 1.47)
• 3.17 (-5.73, -0.61)

0.009

• 4.37 (-6.85, -1.88)

<0.0001

PSQI (z-score)

• 0.88 (-1.67, -0.10)^
• 0.87 (-1,68, -0.09)^
• 0.07 (-1.03, 0.49)
• 0.01 (-1.11, 1.12)

>0.99

• 0.61 (-1.70, 0.48)

0.538

PSEQ#

3.16 (0.75, 5.57)^^ 1.51 (-0.94, 3.96) 0.82 (-1.5, 3.15) 1.65 (-1.79, 5.09) 0.745 2.34 (-1.01, 5.69) 0.281

PCS

• 3.38 (-5.32, -1.45)^^
• 3.12 (-5.09, -1.15)^^
• 1.39 (-3.26, 0.48)
• 0.26 (-3.03, 2.50)

>0.99

• 1.99 (-4.69, 0.70)

0.226

TSK

• 0.73 (-2.04, 0.59)
• 0.34 (-1.68, 1.00)
• 0.18 (-1.45, 1.09)
• 0.39 (-2.26, 1.49)

>0.99

• 0.55 (-2.38, 1.28)

>0.99

SF-36 MCS#

2.32 (0.21, 4.43)^ 1.24 (-0.91, 3.39)

• 0.04 (-2.08, 2.00)

1.08 (-1.94, 4.09) >0.99 2.36 (-0.58, 5.30) 0.164

SF-36 PCS#

2.37 (1.05, 3.70)^^ 1.15 (-0.20, 2.50) 1.37 (0.09, 2.65) 1.22 (-0.67, 3.12) 0.359 1.00 (-0.84, 2.84) 0.574

PROMIS- Anxiety

• 1.07 (-2.59, 0.46)
• 0.57 (-2.12, 0.98)
• 0.66 (-2.14, 0.82)
• 0.05 (-2.68, 1.68)

>0.99

• 0.41 (-2.53, 1.72)

>0.99

PROMIS- Depression

• 2.84 (-4.18, -1.49) ^^
• 0.09 (-1.47, 1.28)

0.38 (-0.92, 1.68)

• 2.71 (-4.66, -0.82)

0.002

• 3.22 (-5.09, -1.35)

0.0001

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Active TENS n=103 Placebo TENS n=99 No TENS n=99 Group Mean Difference (95% CI) P-value Active vs PLACEBO Active vs No TENS

Self-report function

• utcomes

FIQ-R Function

• 2.71 (-4.00, -1.42)^^
• 1.38 (-2.70, -0.06)^
• 0.56 (-1.81, 0.68)
• 1.33 (-3.18, 0.51)

0.073

• 2.15 (-3.94, -0.36)

0.005

SF-36 Physical Function

1.39 (0.10, 2.69)^ 0.53 (-1.79, 1.84) 0.75 (-0.50, 2.00) 0.86 (-0.98, 2.71) >0.99 0.65 (-1.15, 2.44) >0.99

Performance- based function

• utcomes

6MWT

0.06 (-0.49, 0.61)

• 0.11 (-0.66, 0.44)
• 0.34 (-0.87, 0.19)

0.17 (-0.61, 0.95) >0.99 0.40 (-0.36, 1.17) >0.99

Functional reach

0.16 (-0.42, 0.74) 0.04 (-0.55, 0.63)

• 0.13 (-0.69, 0.44)

0.29 (-0.60, 1.18) >0.99 0.29 (-0.60, 1.18) >0.99

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A c t i v e

• T

E N S P l a c e b

• T

E N S N

• T

E N S 50 100 Global Rating of Change Percent

TENS improves global rating of change

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Active TENS n=103 Placebo TENS n=99 No TENS n=99 P-value (adjusted) Responder Definitions Active vs Placebo Active vs No TENS ≥30% Reduction pain 44% (34-53) 22% (15-31) 14% (9-22) 0.004 <0.001 ≥20% Reduction fatigue 45% (35-54) 26% (19-36) 23% (16-33) 0.019 0.004 ≥20% Reduction function 38% (29-48) 36% (28-46) 28% (20-38) 0.974 0.319 ≥30% Reduction pain + ≥20% fatigue 29% (21-39) 13% (8-21) 13% (8-21) 0.018 0.018

Responder Analysis

Strongest predictor of pain response was reduction of MEP during first TENS treatment

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Other Results

• No difference in ITT compared with per protocol analysis
• PP: At least 30 min/d for 8 sessions over 4 weeks
• Placebo TENS and No TENS groups had similar beneficial results

after 4 weeks open-label Active TENS

• Active TENS group had sustained/improved outcome after an

additional 4 weeks open-label treatment

• No significant reduction in effectiveness of TENS in opioid versus

non-opioid strata

• TENS-related adverse effects
• Skin irritation from electrodes
• Anxiety, nausea
• Pain (muscle spasm, unspecified)
• NNH between 20 and 100

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Summary

• Active TENS improves resting and movement-evoked pain

and fatigue acutely

• No TENS tolerance develops over 4-8 weeks of treatment
• After 4 weeks of treatment, there was evidence of a chronic

TENS effect with a reduction in baseline pain and fatigue

• Active TENS resulted in global improvement of disease

impact

• There was improvement in one measure of depression, but

no significant effect of TENS on measures of function, sleep,

• r other clinical domains
• There were minimal adverse effects associated with TENS

treatment

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Pragmatic Trial

Fibromyalgia – TENS in Physical Therapy Study (FM-TIPS)

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Study Team

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Study Overview

• Goal:
• Demonstrate the feasibility of adding TENS to treatment of

patients with FM in a real-world Physical Therapy practice setting and

• Determine if addition of TENS to standard Physical Therapy for

FM reduces pain, increases adherence to PT and allows patients with FM to reach their specific functional goals with less drug use.

• Hypothesis
• Using TENS in a Physical Therapy setting is feasible and that FM

patients using TENS are more likely to reach their therapeutic goals.

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cluster-randomized pragmatic trial routine PT with or without TENS for FM enroll ~600 people with FM

Specific Aims

Aim 1: Determine if addition of TENS to routine PT improves movement-evoked pain Aim 2: Determine if addition of TENS to routine PT improves 1) disease activity, 2) likelihood of meeting patient-specific functional goals, 3) adherence to PT, and 4) medication use Aim 3: Examine feasibility of implementing TENS into routine PT care for FM using semi- structured exit interviews of patients and PTs

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Study Design

• Physical therapy setting
• PT are familiar with TENS
• TENS may be most helpful when used during movement
• More frequent “touches” with patients may facilitate compliance
• Cluster randomized
• Five PT health systems – Iowa, Illinois, Tennessee
• Twenty-four PT sites
• Each site randomized to TENS + PT or PT only
• Stratified randomization by health system and site size
• Versus constrained randomization
• Pragmatic design
• Inclusion/exclusion criteria
• Minimal interference with usual care
• Emphasis on PRO
• Intervention
• TENS (Quell) x 2 applied to cervical/low back regions recommended for 2h

daily during activity

• Mixed frequency, strong but comfortable intensity

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Visit Schedule

PT V1 Home PT V2 Home PT V3-PT completed Home Days 30, 60, 90, 180

• Identify eligible

participants

• Provide study

materials and REDCap access

• Develop

treatment plan

• Review study

materials

• Sign e-Consent
• Check that

consent is signed

• Provide TENS
• Collect

baseline pre- TENS data

• First TENS

treatment

• Collect

baseline post- TENS data

• Check that

baseline data entered

• Provide

treatment

• Primary endpoint

Day 60

• TENS provided to

no-TENS randomized participants if data completed

Pre-Resting NRS pain/fatigue, Pre-MEPT with NRS mvmt pain/fatigue, TENS applied for 1st full treatment (or not) x 30 min, Demographic data, 2016 FM criteria, FIQR, MAF, BPI, PROMIS PhysFunct, PROMIS Sleep, Sleep Duration, PCS, PHQ-8, GAD-7, TAPS1, Medications, RAPA, Post Resting NRS pain/fatigue, Post MEPT with NRS mvmt pain/fatigue, Adverse event, Barriers to TENS

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Outcome measures

• Primary outcome: Movement evoked pain
• Baseline: Five times sit-to-stand pre-TENS
• Primary endpoint: 5TSTS after 30-min TENS at day 60
• TENS + PT vs PT only
• Power analysis  600 participants
• Secondary outcomes
• Other PRO
• PT adherence
• Descriptive comparisons
• Baseline vs days 90, 180: TENS + PT (long-term use) and PT-only

followed by TENS started at home

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Challenges

• PT sites not used to conducting embedded research
• Multiple different EHR
• Data collection limited
• COVID impact on free-standing PT practices
• Changes in volumes, financial issues
• Rolling starts of PT systems

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Conclusions

• TENS can be safely used in addition to other treatments

to improve pain and fatigue in women with fibromyalgia in the setting of an RCT

• Practicality of using TENS for patients with fibromyalgia

referred for PT needs to be determined

• Is TENS uptake improved if applied during PT treatment?
• Effectiveness of TENS in a real-world type setting remains

to be determined

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Comments or Questions?